Synthesis and Characterization of 5, 6 Diphenyl Pyrrole Derivatives and it s Pharmacological Profile

Transcription

1 Available online at Journal of Current arma esearch 4 (3), 2014, riginal esearch Article Synthesis and Characterization of 5, 6 Diphenyl Pyrrole Derivatives and it s armacological Profile P.B. Khulpe*, S.K. Mohite Department of armaceutical Chemistry, ajarambapu College of armacy Kasegaon, Tal- Walwa, Dist- Sangli , Maharashtra, India eceived 26 April 2014; received in revised form 12 May 2014; accepted 12 May 2014 Available online 23 June 2014 Abstract ovel series of pyrrole derivatives were synthesized with an approach to develop more potent and less side effects having antimicrobial anti-inflammatory and anti-tubercular. An efficient synthesis of different novel 2-methyl-7(4-nitrophenyl)-5,6 diphenyl-3,7 dihydro-4h-pyrrolo [2,3-d]pyridine-4-one derivatives by the Paal-knorr Condensation. Benzoin with primary aromatic amines refluxing in ethanol resulted the formation of α-aminoketone intermediates, which were condensed, without isolation, with malononitrile to yield the various 2-amino-4,5-diphenyl-1-substituted-1H-pyrrole-3- carbonitriles (Ia-e). Pyrrole (Ia-e) further reacted with acid such as acetic acid to yield compound (IIae). The synthesized compounds were confirmed through spectral characterization using I (JASC 4100-FT/I), Mass (QP 2013 Shimadzu) and 1H M. esult indicated that these compounds showed promising antimicrobial activity, anti-tuberculosis activity and anti-inflammatory activity in comparison to standard drugs was used. Keywords: Pyrrole derivatives, acetic acid, antimicrobial activity, anti-tuberculosis and antiinflammatory activity. 1. Introduction armaceutical chemistry is a scientific discipline at the intersection of chemistry and pharmacy involved with designing and developing pharmaceutical drugs. These are chemical compounds that may be used in diagnosis, treatment, cure and mitigation of disease or other abnormal conditions. Pyrrole derivatives are display diverse biological activity. In the preparation of pyrrole derivative many disadvantages including harsh reaction condition and poor yields by applying Paal- Knorr reaction. Pyrrole derivatives are considerable attention of synthetic importance and extensively used in drug discovery and pharmacological activity such as antimicrobial 6,7 anti-inflammatory and antitubercular 2. Corresponding author. address: priyakhulpe@rediffmail.com (P.B.Khulpe) e / 2014 JCP. All rights reserved. 2. Experimental Synthesis of substituted 5,6-diphenyl pyrrole derivatives was carried out in two steps. 1] Synthesis of 2-amino-5,6-diphenyl-1- substituted-1h-pyrrole-3carbonitrile [Ia-e]. 2] Synthesis of derivatives [IIa-e] Step 1 1. Synthesis of 2-amino-4, 5-diphenyl-1- substituted-1h-pyrrole-3carbonitrile [Ia-e]. A mixture of benzoin, the appropriate amine aniline and conc. HCl in ethanol was heated under reflux and cooled. Malononitrile was added, followed by a catalytic amount of pyridine portion wise and left to reflux until a solid formed. The solvent was evaporated under reduced pressure and the residue was recrystallized from methanol. Yield: 63-69% MP ⁰C. 1181

2 P.B.Khulpe et al. / Journal of Current arma esearch 4(3), 2014, Step 2: Synthesis of 2-methyl-7-(amine)-5, 6 diphenyl-3, 7-dihydro-4H-pyrrolo [2, 3-d] pyrimidin-4-one. [IIa-e] The appropriate, 2-amino-4,5-diphenyl-1- substituted-1h-pyrrole-3carbonitrile [Ia] in acetic acid was refluxed for 3 h, cooled, poured onto ice water, filter off dried to give 2- methyl-7-(amine)-5,6 diphenyl-3,7-dihydro-4hpyrrolo [2,3-d]pyrimidin-4-one [ IIa-e] and recrystallized from methanol. 1. Synthesis of 2-methyl-7-(4-nitrophenyl)-5, 6 diphenyl-3, 7-dihydro-4H-pyrrolo [2,3- d]pyrimidin-4-one.[iia] I (cm -1 ): 3356(H Str), 3030(Aro C-H), 2350(Aryl nitro), 1710(C=), 1680(C=), 1450(C-); M (δ, ppm): (m, Ar-14H of 4,5 diphenyl ring), 4.6(s,1H CH3 of pyrimidin). 2. Synthesis of 2-methyl-7-(4-bromophenyl)- 5,6 diphenyl-3,7-dihydro-4h-pyrrolo [2,3- d]pyrimidin-4-one. [IIb] I (cm -1 ): 3400(H Str), 3020(Aro C-H str), 1705(C=), 1610(C=), 1460(C-), 470(Arobr); M (δ, ppm): 3. Synthesis of 2-methyl-7-(4-ethylphenyl)-5, 6, diphenyl-3, 7-dihydro-4H-pyrrolo [2, 3-d] pyrimidin-4-one. [IIc] 4. Synthesis of 2-methyl-7-(2,4 dinitrophenyl)- 5,6 diphenyl-3,7-dihydro-4h-pyrrolo [2,3- d]pyrimidin-4-one. [IId] 5. Synthesis of 2-methyl-7-(, dimethylphenyl)-5, 6 diphenyl-3, 7-dihydro-4Hpyrrolo [2, 3-d] pyrimidin-4-one. [IIe] The appropriate aminopyrrole, Ie in acetic acid was refluxed for 2 h, cooled, poured onto ice water, filter off dried to give IIe and recrystallized from methanol. H + H 2 C 2 H 5 H HCl H anilino - 1,2 diphenyl Benzoin substituted aniline C - CH 2 - C Acetic acid/hcl C H 3 C H II a - e H 2 Ia - e Where, =P-nitro, P-bromo, 4-ethyl, 2,4dinitro, dimethyl aniline. Scheme 1182

3 P.B.Khulpe et al. / Journal of Current arma esearch 4(3), 2014, ame Table 1: Properties of Synthesized Compound. Molecular formula f value % yield Melting Point IIa C25H ⁰C IIb C25H183Br ⁰C IIc C27H ⁰C IId C25H ⁰C IIe C27H ⁰C Anti-Microbial activity their invitro antimicrobial activity against E. coli, S. aureus, B. substilis and S. typhi by disk diffusion method was performed using MacConkeys agar and utrient agar medium. Each compound was tested at a concentration at 100µg/ml in DMS. The zone of inhibition was measured after 24h incubation at 37⁰C. Anti-tubercular activity their invitro antitubercular activity against Mycobacterium TB H37V by nitrate reductase assay method was performed using LJ media. Each compound was tested at a concentration at 100µg/ ml, 150 µg /ml and 200µg/ ml in DMS. If bottles didn t show any colour change and remain the same then it was confirmed that M.TB H37V it was sensitive to that test samples. Anti-inflammatory activity their invitro anti-inflammatory activity by Protein denaturation method. The reaction mixture consisted of 0.4ml egg albumin, 5.6ml phosphate buffer saline (ph6.4) and 4ml varying concentration of compounds. Each compounds was tested at a concentration at 50 µg /ml in DMS. Mixture were incubated at 37⁰C and then heat at 70⁰C.after cooling, there absorbance was measured at 660 nm, by using vehicle as a blank and their viscosity was determined by using stwald viscometer. Diclofenac sodium 50 µg /ml was used as reference drug and treated similarly for determination of absorbance and viscosity. esults and Discussion Experimental I] Synthesis of 2-methyl-7-(4-nitrophenyl)-5, 6 diphenyl-3, 7-dihydro-4H-pyrrolo [2, 3-d] pyrimidin-4-one. [IIa] II] Synthesis of 2-methyl-7-(4-bromophenyl)-5, 6 diphenyl-3, 7-dihydro-4H-pyrrolo [2, 3-d] pyrimidin-4-one. [IIb] III] Synthesis of 2-methyl-7-(4-ethylphenyl)-5, 6 diphenyl-3, 7-dihydro-4H-pyrrolo [2, 3-d] pyrimidin-4-one. [IIc] IV] Synthesis of 2-methyl-7-(2, 4 dinitrophenyl)-5, 6 diphenyl-3, 7-dihydro-4Hpyrrolo [2, 3-d] pyrimidin-4-one. [IId] V] Synthesis of 2-methyl-7-(, dimethylphenyl)-5, 6 diphenyl-3, 7-dihydro-4Hpyrrolo [2, 3-d] pyrimidin-4-one. [IIe] The step 1 reaction afforded the yield of product (Ia-e) in the range of 63-69% and time taken by this method is 5-7h. The step 2 reaction afforded the yield of product (IIa-e) in the range of 55-71% and time taken by this method is 2-5h. I, MASS, M Spectra studies The structural elucidation of the synthesized compounds was done by the interpretation of I, MASS and M spectra s. All the compounds show satisfactory I, MASS and M. armacological Studies Graph o. 1: The Antimicrobial activities of synthesized compounds (IIa-e) %inhibition = [control-test/control] x

4 P.B.Khulpe et al. / Journal of Current arma esearch 4(3), 2014, Graph 1: The Antimicrobial activities of synthesized compounds (IIa-e) Where Standard (ampicilin) showed highly active against E.coli, S.aureus, B.Substilis, and S.typhi. IIc and IIe showed highly active compounds, IIa, IIb showed moderately active compounds while IId showed inactive compounds against E.coli. IIb showed highly active compounds, IId and IIe showed moderately active compounds while IIc inactive compounds against S.Aureus. IIb showed highly active compounds, IIc and IId showed moderately active compounds while IIa and IIe showed inactive compounds against B.Substilis. IIa showed highly active compounds, IIe showed moderately active compounds while IIb, IIc and IId showed inactive compounds against S.typhi. Table 2: Antitubercular Activity. Comp. Concentration (µg/ml) ame IIa C C C IIb C C C IIc C C C IId C C C IIe C C C Control Yellowish pink colour Standard C (Isoniazide and ifampicin) Where, C-Change, C-not change. From the observation of itrate eductase Assay it has been showed that the compounds IIa and IIc are active against M.tuberculosis H37V as compare to standard drugs ifampicin and Isoniazid. Table 3: Effect of pyrrole derivatives on protein denaturation. Compound o. Concentration(µg/ml) % Inhibition Viscosity(cps) Control Standard IIa IIb IIc IId IIe Denaturation of proteins is a well documented cause of inflammation and rheumatoid arthritis. Production of auto antigens in certain arthritic disease may b due to denaturation of proteins invivo. Several anti-inflammatory drugs have shown dose dependent ability to inhibit thermally induced protein denaturation. It has been reported that one of the features of several non-steroidal anti-inflammatory drugs is their ability to stabilize (prevent denaturation) heat treated albumin at the physiological ph. This anti-denaturation effect was further supported by the change in viscosities. It has been reported that the viscosities of protein solutions increase on denaturation. In the present study, the relatively high viscosity of control dispersion substantiated this fact. Ability of pyrrole derivatives to bring down thermal denaturation of protein is possibly a contributing factor for its anti-inflammatory activity. 1184

5 P.B.Khulpe et al. / Journal of Current arma esearch 4(3), 2014, eferences [1] Mosaad Mohamed et al. European Journal of Medicinal Chemistry, 46 (2011) [2] agno et al. Bioorganic Medicinal Chemistry, 8 (2000) [3].K.Bansal. Heterocyclic chemistry, 4 (2005) [4] Anna Maria Almerico. Bioorganic and Medicinal Chemistry, 13 (2005) [5] T.M. Patel. International Journal of armaceutical esearch and Allied Sciences, 4 (2012) [6] M.S.Mohamed. Acta pharma, 59 (2009) [7] A.Idhayadhulla et al. Der arma Chemica, 3 (2011) [8] K. Anzai, S. Marumo. J. Antibiot, 10A (1957) 20. [9] C.J. Shishoo, G.V. Ullas, V.S. Bhadti, M.B. Devani, S. Ananthan. J. Heterocycl. Chem., 18 (1981) 43. [10] A.. Katriski, Ji Fu-Bao, W. Fan, J.K. Gollas, J.V. Greenhill,.W. King, J. rg. Chem., 57 (1992) 190. Source of Support: il. Conflict of Interest: one declared ********** 1185